The psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC), binds cannabinoid receptors that are part of an endogenous neuromodulatory system. Recent progress in studying this system has revealed that endocannabinoids are released by postsynaptic neurons following depolarizing stimuli. The released endocannabinoids then act in a retrograde fashion on the presynaptic terminal to inhibit neurotransmitter release. In the previous funding period we studied the presynaptic effects of cannabinoids noting that these drugs display a range of efficacies, that prolonged exposure to them results in desensitization and that they affect synaptic plasticity. We propose to extend these findings by determining how modulation of presynaptic cannabinoid receptors affects retrograde endocannabinoid signaling. Specifically we will study depolarization-induced suppression of excitation (DSE) in the hippocampal slice preparation to test three hypotheses, 1) We will use pharmacological approaches to test the hypothesis that DSE observed in hippocampal CA1 neurons is mediated by retrograde endocannabinoid signaling. 2) We will test the hypothesis that THC, a partial agonist, will both attenuate and occlude endocannabinoid retrograde signaling. 3) We will test the hypothesis that desensitization of presynaptic cannabinoid receptors will raise the stimulus intensity required to evoke DSE. These studies will enhance our understanding of how cannabinoids affect synaptic transmission. In particular, they will reveal how exogenous cannabinoids affect endogenous cannabinoid signaling. Recent evidence suggests that the endocannabinoid system participates in the development of dependence to multiple classes of abused drugs. These studies will provide insight into how endocannabinoid signaling adapts to drugs of abuse.